Programmed death-1 (PD1, CD279) is a member of the CD28 superfamily that negatively regulates the function of T cells through interaction with its two native ligands PD-L1 (CD274) and PD-L2 (CD273). PD1 is a type I transmembrane receptor protein composed of a single immunoglobulin (Ig) variable-like domain, a cytoplasmic domain, and two tyrosine-based signaling motifs. The ligands for PD1 are PD-L1 (CD274 or B7-H1) and PD-L2 (CD273 or B7-DC), which are members of the B7 family.
PD-L1 is found expressed on both hematopoietic and non-hematopoietic cells found in immunoprivileged sites including the eye and placenta, and is highly elevated in inflammatory environments. Following activation of an immune response, antigen presenting cells (APCs) and T cells further augment the expression of PD-L1, while PD-L2 expression is only found on activated macrophages and DCs. PD1 is constitutively expressed at low levels on resting T cells and is up-regulated on T cells, natural killer T (NKT) cells, B cells and macrophages upon activation.
The absence of PD1 in mice provides significant resistance against bacterial infection through innate immunity, demonstrating the importance of the regulatory role of PD1 against pathogenic infections. In addition, PD1 plays significant roles in a number of autoimmune diseases, including systemic lupus erythematosus (SLE) and rheumatoid arthritis.
Recent studies have characterized the inhibitory function of the interaction between PD1 and PD-L1/2. With PD1 deficient transgenic mice, CD8+ T cells were found to recognize H-2Ld and proliferate more actively than wildtype cells in response to allogeneic (H-2d) APCs. In addition, PD1 deficient mice develop spontaneous lupus-like disease and cardiomyopathy, indicating that PD1 has the role to control over-activated T cells. This is more evident from a study that found up-regulated PD1 expression on LCMV-specific CD8+ T cells, which directly contributes to the dysfunction of these T cells and correlated with the failure to control viral replication in mice during chronic infection. It has been known that HIV-1-specific T cells in patients are usually poorly functional due to the loss of CD28 co-stimulatory molecule, perforin, and down-regulation of CCR7 and IL-7Rα, which are important molecules for maintenance of memory T cells. One of the reasons for the exhausted T cell function during HIV-1 infection is attained by recent studies showing that PD1 is persistently up-regulated on HIV-1 specific CD4+ and CD8+ T cells that have reduced proliferation, cytokine production, and cytotoxicity.
The role of the PD1/PD-L pathway in chronic infections (Mycobacterium tuberculosis, LCMV, HIV-1, HBV and HCV) has been characterized extensively. The high expression of PD1 on pathogen-specific CD8+ T cells results in these cells being functionally “exhausted,” leading to the failure of clearing persistent infections. In addition, the blockade of the PD1/PD-L1 pathway in vitro and in vivo with antibody or the soluble form (i.e., only containing extracellular domain) of PD1 is able to rescue the function of these exhausted HIV-1 and HCV specific CD8+ and CD4+ T cells by restoring cytokine production, cell proliferation, and cytolysis.
Progression towards AIDS is markedly correlated with the level of PD1 expression on HIV-1-specific CD8+ T cells and the percentage of cells expressing PD1 with viral load and declining CD4+ counts. In contrast, long-term non-progressors (LTNPs) have significantly lower level of PD1 expression found on HIV-specific memory CD8+ T cells compared to progressors.
Experiments also demonstrated that blockade of the PD1/PD-L1 interaction can reverse the function of these exhausted viral-specific CD8+ T cells, which was further shown in vivo in LCMV chronically infected mice treated with antibodies against PD1/PD-L resulted in LCMV-specific CD8+ T cells with restored proliferation and TNF-α and IFN-γ production that led to reduced viral load. Other studies also found that highly active antiretroviral therapy (HAART) recovered reduced PD1-expressed HIV-1-specific CD8+ T cells, and that blocking of the PD1/PD-L pathway could rescue the function of HIV-1-specific T cells. These findings show the importance of the PD1/PD-L pathway that results in the exhausted state of T cells during HIV-1 chronic infection, and may act as one of the key host factors in modulating immune response to target HIV-1 infected cells.
To date, four PD1 isoforms have been reported from alternatively spliced PD1 mRNA. Apart from one of these variants encoding a soluble form of PD1, the other three spliced variants have no function attributed to them. Nevertheless, their highly induced expression following stimulation of human peripheral blood mononuclear cells (PBMCs) likely suggests an immunoregulatory function, which has been shown for variants of the other CD28 family molecules, such as CTLA-4 and CD28. One isoform of CTLA-4 (1/4CTLA-4) could exacerbate experimental autoimmune encephalomyelitis (EAE) diseases in mice, with significantly increased level of CD4+ T cell proliferation and cytokine production compared to wildtype CTLA-4. Interestingly, over-expression of this variant resulted in the down-regulation of wildtype CTLA-4 on CD4+ T cells. For CD28, four spliced variants were identified from human T cells with differential expression. The CD28i isoform was found expressed on the cell surface where it could associate with CD28 to enhance the co-stimulation capacity via CD28, further illustrating that apart from the conventional identified forms, spliced variants of the CD28 receptor family members could have immunoregulatory functions.